6-fluoro steroids and process for preparing same



United States atent O G-FLUORO STEROIDS AND PROCESS FOR PREPARING SAME George B. Spero, Kalamazoo Township, Kalamazoo County, Barney J. Magerlein, Kalamazoo, and William P. Schneider and John A. Hogg, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application November 29, 1957 Serial No. 699,501

27 Claims. (Cl. 260397.45)

This invention relates to 1-dehydro-6-fluoro-9a-halo- 2l-desoxyhydrocortisone and 1-dehydro-6-fluoro-9a-halo- 2l-desoxycortisone and is more particularly concerned with 1 dehydro-6a,9a-difiuoro-2l-desoxyhydrocortisone (600,90: difiuoro 115,17 dihydroxy-1,4-pregnadiene- 3,20-dione) and 1-dehydro-6a,9a-difiuoro-2l desoxycortisone (604,90: difluoro 17oz hydroxy-1,4-pregnadiene- 3,11,20-trione), and to processes for the production thereof.

The compounds of this invention, l-dehydro-G-fluoro- 9a-halo-21-desoxyhydrocortisone and l-dehydro-G-fluoro- 9whale-21-desoxycortisone, possess valuable anti-rheumatoid arthritic, anti-inflammatory and glucocorticoid activities in marked degree. Thus, for example, l-dehydro-6a,9a-difluoro-21-desoxyhydrocortisone has been found to exhibit approximately sixty to seventy times the anti-inflammatory activity of hydrocortisone, and in addition has a favorable effect on salt and Water balance. These compounds are useful in the treatment of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic animals, as Well as contact dermatitis and other allergic reactions' Administration of the novel steroids can be in conventional dosage forms, such as pills, tablets, capsules, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic cortical steroid hormones for injectable products. The novel compounds can also be administered topically in the form of ointments, creams, lotions and the like, with or without coacting antibiotics, germicides or other materials forming advantageous combinations therewith.

The compounds of this invention can be prepared in accordance with the following reactions:

Patented June 10, 1.1958

wherein X is a halogen of atomic weight between seventeen and eighty, inclusive, i. e., fluorine, chlorine, or bromine and wherein R is an organic radical, particularly a hydrocarbon radical containing from one to ten carbon atoms, inclusive, such as methyl, ethyl, phenyl, tolyl, naphthyl, or the like, methyl being preferred.

It is an object of the present invention to provide 1- dehydro-6-fiuoro-9o-halo-2l-deisoxyhydrocortisone (IV) and 1-dehydro-6-fluoro-9a-halo-2l-desoxycortisone (V). Another object of this invention is to provide l-dehydro- 6a,9a-diflu0ro-2l-desoxyhydrocortisone and l-dehydro- 6a,9wdifluoro-2l-desoxycortisone A further object is to provide a process for the production of l-dehydro-6- fluoro-9a-halo-2l-desoxyhydrocortisone and l-dehydro- 6-fluoro-9a-halo-2l-desoxycortisone. An additional object is to provide a process for the production of l-dehydro-6a,9a-difluoro-2l-desoxyhydrocortisone and l-dehydro-6u,9a-difluoro-2l-desoxycortisone.

The process of the present invention comprises treating a 6-fluoro-9u-halo-l1fi,17a, 21-trihydroxy-L4-pregnadiene 3,20 dione (l dehydro-6-fiuoro-9a-halohydrocortisone) (I) with an organic sulfonyl halide to obtain the corresponding 21-ester (II), a 21-alkyl or aryl sulfonate of 6-fluoro-9oa-halo-11B,17u,2l-trihydroxy-L4- pregnadiene-3,20-dione, and thereafter treating the thus produced 21-alkyl or aryl sulfonate with an iodinating agent, such as sodium iodide in acetone solution, to obtain the corresponding 6-fluoro-9u-halo-2l-iodo-l 1 3,170;- dihydroxy-1,4-pregnadiene-3,ZO-dione (III), and finally, treating the thus produced 6 -fluor0-9oz-h8lO-2l-i0d0- l1,8,l7m-dihydroxy-1,4-pregnadiene-3,20-dione with a reducing agent, such as zinc dust, sodium thiosulfate, sodium bisulfite, potassium bisulfite, or the like, in an aqueous 2, 38,588 A p r organic solvent mixture, to obtain 6-fluoro-9a-hal0 11,8,17a-dihydroxy-1,4-pregnadiene-3,20 dione (IV). The 6-fiuoro-9a-halo product above can be oxidized to give the corresponding 6-fiuoro-9a-halo-17q-hydroxy-1,4- pregnadiene-3,11,20-trione (V). Similarly, when the 11- keto analogue (6-fiuoro-9a-halo-l7ot,2l-dihydroxy-l,4 pregnadiene-3,11,20-trione) is utilized as starting material in the above series of reactions, 6-fluoro-9u-halo- 17a-hydroxy-1,4-pregnadiene-3,11,20-trione (V) is produced directly without the necessity for oxidation of the 1 l/8-hydroxyl.

The starting steroids for the compounds and process of the present invention are 1-dehydro-6-fluoro-9u-halohydrocortisone and 1-dehydro-6-fiuoro-9a-halocortisone and are prepared in accordance with the procedures of Preparations 1 through 21 herein. The preferred compounds containing the 17(20)-double bond have the cis configuration because they are convertible in higher yields in the oxidative hydroxylation step than are the trans isomers, although both are operative.

In carrying out the process of this invention, l-dehydro- 6-fluoro-9a-halohydrocortisone is treated with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl. chloride, toluenesulfonyl bromide, benzene-sulfonyl chloride, naphthylsulfonyl chloride, and the like, the methanesulfonic acid halides, especially methane-sulfonyl chloride, being preferred. In the preferred embodiment of this invention, the starting steroid is usually reacted with the alkyl or aryl sulfonyl halide in solution in a solvent such as pyridine, benzene, toluene, or the like. Where such solvents as benzene and toluene are employed, an amount of an amine base such as pyridine at least equal to the molar amount of the sulfonyl halide should also be present to react with the halogen acid formed. Reaction of the alkyl or aryl sulfonyl halide is conducted preferably at temperatures between minus ten and plus sixty degrees centigrade, provided that at the lower temperatures the solvent has not solidified. Thus, for pyridine, dioxane, toluene, or the like, temperatures in the range of zero to ten degrees centigrade can be used, while for benzene only temperatures above five degrees centigrade are suitable because of the relatively high freezing point of benzene. The reaction time is usually between about four and 24 hours, after which the product,

6-fluoro-9a-halo1 1/3,17a,21-trihydroxy-1,4 pregnadiene- 3,20-dione 21-alkyl or aryl sulfonate (II), is recovered in a conventional manner, such as, for example, by evaporating the solvent until a dry residue is obtained or by diluting the reaction mixture with water and precipitating the product with dilute hydrochloric acid.

The 6-fluoro-9a-halo-1 1,8,17a,21-trihydrovy-1,4-pregnadiene-3,20-dione 21-alkyl or aryl sulfonate is converted to the corresponding 21-iodo compound (IV), by reacting the said 21-alkyl or aryl sulfonate with an iodinating agent, such as an alkali metal iodide, e. g., sodium, potassium or lithium iodide, in an oxygenated hydrocarbon solution such as an alkanone solution, e. g., acetone. A molar excess of the iodide (three to twenty moles of iodide per mole of steroid) is preferred for this reaction. The reaction mixture containing the 21-alkyl or aryl sulfonate and the alkali metal iodide in solution is heated to reflux for a period of about three minutes to thirty minutes. The thus produced 6-fiuoro-9a-halo-21-iodol1,6,17u-dihydroxy-l,4-pregnadiene-3,20-dione can then be isolated by evaporating the solvent. For the subsequent reaction, the 21-iodo steroid can be used either in purified form as a product of recrystallization from such organic solvents as acetone, ethanol, and the like, or it can be employed directly as a crude product in the next step of the synthesis.

In order to obtain 6-fluoro-9a-halo-11fl,17u-dihydroxy 1,4 pregnadiene-3,20-dione, 6-fluoro-9a-halo- 11B,17a-dihydroxy-21-iodo-1,4-pregnadiene-3 ,20-dione is reacted with a reducing agent such assodium or potassium thiosulfate, sodium bisulfite or zinc dust in acetic acid. In

the preferred embodiment of the invention the 21-iodo compound is dissolved in acetic acid at room temperature and stirred from about thirty minutes to one hour. Excess aqueous sodium thiosulfate is added, followed by ice and water. The time of reaction is not critical and is generally between a few minutes and several hours. The amount of sodium thiosulfate can be varied so long as an excess is used. The product, 6-fll1O1'0-90c-h310-11fi,17otdihydroxy-l,4-pregnadiene-3,20-dione, is obtained by conventional means such as recrystallization, or extraction and thereafter recrystallization, or chromatography as deemed necessary.

The foregoing reactions can likewise be conducted on the corresponding ll-keto analogues.

The oxidation of 6-flL10IO-9cc-hfilO-1113,17ot-dihYdl0XY- l,4-pregnadiene-3,20-dione can be carried out by a variety of methods, such as, for example, by oxidizing the said steroid in acetic acid solution with chromium trioxide, using molar quantities or a slight excess, such as from ten to thirty percent excess, or by oxidizing with a haloamide or imide of an acid, such as N-bromoacetamide, N- chloro-succinimide, or N-bromosuccinimide dissolved in pyridine, dioxane, or other suitable solvents. At the conclusion of the desired oxidation reaction, the excess oxidant is generally destroyed by addition of methyl alcohol, ethyl alcohol, and the like for the chromic acid oxidant or a bisulfite for N-bromoacetamide, N-bromosuccinimide and other N-halo acyl amides and imides. Thereafter, the resulting 6-fiuoro-9a-halo-17a-hydroxy-1,4-pregnadiene- 3,11,20-trione is recovered by conventional means, such as by extraction with water-immiscible solvents, e. g., methylene chloride, ether, benzene, toluene or the like, or by chromatography.

The order of steps for the preparation of the products of the present invention are susceptible of variation without departing from the basic concepts of the process. AS shown in Preparations 12 through 15, 1-dehydro-6-fluorohydrocortisone is converted to 1-dehydro-6-fluoro-9ahalohydrocortisone by the introduction of the 9a-halogen. The 1-dehydro-6-fiuoro-9u-halohydrocortisone is then converted to l-dehydro-6-fiuoro-9a-halo-2l-desoxyhydrocortisone as shown in the examples. Alternatively, if desired, removal of the oxygen at carbon atom 21 can be done first, and this can be followed by halogenation at carbon atom 9. Thus by treating 1-dehydro-6-fluorohydrocortisone with an organic sulfonyl halide to obtain the corresponding 2l-ester, a 2l-alkyl or aryl sulfonate of 6-fluoro-1lfi,l7a,2l-trihydroxy-l,4-pregnadiene- 3,20-dione, and thereafter reacting the thus produced -21-alkyl or aryl sulfonate with sodium iodide in acetone solution to obtain the corresponding 6-fluoro-11fl,17a-dihydroxy-Zl-iodo-1,4-pregnadiene-3,20-dione, and finally treating the thus produced 21-iodo compound with a reducing agent such as sodium thiosulfate, sodium bisul fite, potassium bisulfite, Zinc dust, or the like in an aqueous organic solvent mixture, there is obtained 6- fluoro-l1,8,17a-dihydroxy-1,4-pregnadiene-3,ZO-dione (1- dehydro-6-fluoro-2l-desoxyhydrocortisone). This product can be dehydrated with N-bromoacetamide and anhy drous sulfur dioxide in pyridine solution by permitting the reaction to continue until a negative acidified potassium iodide-starch test of the recation mixture is obtained. Dilution with cold water results in the precipitation of 6-fiuoro-l7a-hydroxy-1,4,9(11)-pregnatriene-3,20- dione, which can be purified by recrystallization from acetone. The crystalline product can then be reacted in methylene chloride-tertiary butyl alcohol solution with perchloric acid and N-bromoacetamide or N-iodosuccinimide to produce a reaction mixture from which 6- fluoro-9a-bron1o-11t3, 17ot-dihydroxy 1,4 pregnadiene- 3,20-di0ne or the corresponding 6-fillOI'O-9oc-i0d0 compound can be recovered by precipitation with ice water and recrystallization from acetone. The latter steroids can then be reacted in acetone solution with anhydrous potassium acetate at reflux temperatures to produce 6- pregnadiene-3,20-dione. If desired, either the oc-fillOl'O or chloro product can be oxidized, for example, with chromic acid in acetic acid solution to give'6,9rx-difluorovl7rt-hydroxy-1,4-pregnadiene-3,11,20-trione or the correstage and the 6ot-epimer obtained at appropriate interchloric acid. The reduced temperatures should be maintained throughout tlie' period of addition of the acid. The reaction mixture can then be washed with successive portions of dilute alkali and water and evaporated under reduced pressure to obtain the 6wepimer in high yield.

The following preparations and examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

PREPARATION 1 3-eihylene ketal of methyl 3,] 1 -diketo-S a, 6 tit-Oxida- 1 7 (20) cis] -pregn.en-21 -0ate To a solution of five grams of the 3-ethylene ketal of methyl 3,1 1-diketo-4, 17 (20)- [cis]-pregnadien-2l-oate, prepared in the manner described in U. S. Patent 2,707,184, in 100 milliliters of chloroform was added a chilled solution of 1.9 grams of perbenzoic acid dissolved in 31.5 milliliters of chloroform. The solution was maintained at about four degrees centigrade for 24 hours, and then at room temperature for 72 hours. The solution was washed with a five percent aqueous solution of sodium bicarbonate and then with water. The chloroform layer was separated, dried and the solvent distilled to give a residue of 5.3 grams of solid. Crystallization of this solid from methanol gave 2.24 grams of product melting at 180 to 195 degrees centigrade, and after two crystallizations from methanol there was obtained pure 3-ethylene ketal of methyl 3,11 diketo c, 60c oxido 17(20) [cis]- pregnen-Zl-oate melting at 206 to 209 degrees centigrade and having an [04] of plus 37 degrees (CI-ICl and the following analysis:

Analysis.Calculated for C H O C, 69.20; H, 7.75.

, Found: C, 69.59; H, 7.81.

PREPARATION 2 Methyl 5' ,1 I-diketo-Sa, 6B-dihydr0xy-1 7 (20 allopregnen- 21-0ale and methyl 3,1 1-diket0-5a-hydr0xy-6fl-fluor0- 1 7 20 -aZl0pregnen-21 -0aze To a solution of 1.73 grams of 3-ethylene ketal of methyl 3,11-diketo-5a, 6ot-oxido-17(20) [cis] -pregnen- 2l-oate in sixteen milliliters of methylene chloride was added six milliliters of 48 percent hydrofluoric acid. The heterogeneous mixture was stirred for two hours, made slightly basic with 300 milliliters of five percent sodium bicarbonate solution, and extracted with methylene chloride. The extract was washed, dried, and evaporated to dryness to give 1.62 grams of crude solid. Purification by chromatography over synthetic magnesium silicate gave two fractions: A, 481 milligrams eluted with methylene chloride plus five percent acetone, and B, 921 milligrams eluted with methylene chloride plus ten and twenty percent acteone. Crystallization of fraction A from acetone- Skellysolve B hexanes gave 390 milligrams of methyl 3,11- diketo 5a -hydroxy 6(3 fluoro 17(20) allopregnen- 21-oate,'melting point 254 to 260 degrees centigrade. The analytical sample melted at 260 to 263 degrees centigrade.

Analysis.-Calculated for C H O F: F, 4.84. Found: F, 4.47.

PREPARATION 3 Methyl 3,1 1 -diketo-5a-hydraxy-6fl-fluoro-l 7 (20) -all0preghen-21 -0ate I 3-ethylene ketal A mixture of 1.9 grams of methyl 3,11-diketo-5a-hydroxy 6 3 fluoro 17(20) allopregnen 21 oate, 59 milligrams of p-toluenesulfonic acid monohydrate and 31 milliliters of distilled'ethylene glycol was added to 800 milliliters of benzene. The mixture was stirred and refluxed for two hours, with the condensate passing through a water trap to remove the water. After reflux the mixture was cooled, washed with water and evaporated to dryness to give a crude solid which on recrystallization from acetone-Skellysolve B hexanes gave 1.96 grams of methyl 3,11 diketo 50 hydroxy 6 3 fiuoro 17(20)- allopregnen-Zl-oate 3-ethylene ketal, melting point 170 to 173 degrees centigrade.

Following the above procedure, substituting other dihydric alcohols for ethylene glycol, for example, 1,2- propylene glycol, 2,3-butanediol, 1,3-butanediol and 2,3- pentanediol, is productive of the respective 3-alkylene ketals of methyl 3,1 1-diketo-5a-hydroxy-6fi-fluoro-17(20)- allopregnen-Zl-oate.

PREPARATION 4 7 504,1 15,21-trihydroxy-tifi-fluoro-J 7 (20 -allopregn-en- 3-0ne 3-ethylene ketal To a solution of 1.96 grams of methyl 3,11-diketo-5dhydroxy 6B fluoro 17(20) allopregnen 21 oate. 3-

ethylene ketal in 850 milliliters of anhydrous ether was added 3.7 grams of lithium aluminum hydride. The mixture was stirred for a period of one hour, and 200 milliliters of water was added slowly, the ether phase separating. The aqueuous phase was extracted with ethyl acetate and the extracts added to the ether phase. The combined ether-ethyl acetate solution was washed with water, dried and evaporated to dryness under reduced pressure. The crude solid residue was crystallized from acetone-Skellysolve B hexanes to give 1.30 grams of 50,11B,21 tn'hydroxy 6,8 fluoro 17(20) allopregnen-3-one 3-ethylene ketal, melting point 197 to 205 degrees centigrade. An additional 226 milligrams was obtained from the mother liquor, melting point 175 to degrees centigrade.

PREPARATION 5 Similar-1y, other 2l-organic 'carboxylic esters of 5a,ll,8,-'

21 trihydroxy 6;? fluoro 17(20) allopregnen 3- one 3-ethylene ketals can be prepared wherein the 21- acyloxy group is formyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoylo-xy, benzoyloxy, phenylacetoxy, and the like, by contacting 5a,llfl,2l tri'hydroxy 6 fiuoro 17(20) allopregnen- 3-one 3-ethylene ketal with the appropriate acylating agent, e. g., the anhy-dride or acid halide of the selected acid in a solvent such as benzene, toluene, acetic acid, and the like.

PREPARATION 6 To a solution of 0.77 gram of 5a,11B-dihydroxy-6fifiuoro 21 acetoxy 17(20) allopregnen 3 one 3-ethylene ketal in 35 milliliters of tertiary butyl alcohol was added one milliliter of pyridine, 1.9 milliliters of N-methylmorpholine oxide peroxide solution, and 13.1 milligramsof osmium tetroxide (9.1 milliliters of tertiary butyl alcohol solution containing 1.44 milligrams of osmium tetroxide per milliliter). The solution was stirred for a period of 2.5 hours and fifteen milliliters of live per-cent sodium hydrosulfite was added. Stirring was continued for an additional ten minutes, at which time 0.7 gram of finely ground synthetic magnesium silicate was mixed into the solution for a period of twenty minutes and then removed by filtration. The filtrate was evaporated to dryness under reduced pressure at a temperature of less than fifty degrees centigrade. The residue was dissolved in methylene chloride, washed with water, dried and evaporated to dryness. This residue was crystallized from acetone-Skellysolve B hexanes to give 0.47 gram of 504,1lB,17tx-trihydroxy-6 3-fluoro-2lacetoxylallopregnan'e-Fr,20-dione 3-ethylene ketal, melting point 220 to 228 degrees centigrade.

PREPARATION 7 A solution of 0.47 gram of 5a,1l5,l7a-trihydroxy-6B- fiuor21-acetoxyallopregnane-3,20-dione 3-ethylene ketal in 35 milliliters of acetone and four milliliters of 1N sulfuric acid solution was gently boiled on a steam bath for ten minutes, cooled and neutralized with dilute sodium bicarbonate solution. Addition of water followed by cooling gave 0.33 gram of 5a,1le,l7ot-trihydroxy-6flfiuoro-Zl-acetoxyallopregnane-3,20-dione, melting point 230 to 240 degrees centigrade.

PREPARATION 8 6 fl-fl uoro-I 1 3,1 7u-dihydr0xy-21 -acet0xy-4-pregnene-3,20- dione (6 }3fl llorohyd rocortisone acetate) A solution of 100 milligrams of 5a,11B,17a-trihydroxy- 6,8-fluoro-21-acetoxyallopregnane-3,20-dione in 4.9 milliliters of acetic acid and 0.1 milliliter of water was refluxed for a period of one hour, cooled, diluted with fifty milliliters of water and evaporated to dryness under reduced pressure. The residue was chromatographed over synthetic magnesium silicate to give one fraction (77 milligrams) eluted with methylene chloride plus ten percent acetone. Crystallization from acetone-Skellysolve B haxanes gave 38 milligrams of 6fl-fluoro-l1/i,17adihyd-roxy 21 acetoxy 4 pregnene 3,20 dione (6 3-fiuorohydrocortisone acetate), melting point 210 to 218 degrees centigrade. 'Infrared data and ultraviolet data were in agreement with the structure.

PREPARATION 9 6 a-fluoro-l 1 6,1 7e-dihydr0xy-21-acet0xy-4-pregnene-3,20- dione (6 a-fluorohydrocortisone ace rate) A solution of 0.132 gram of 6,8-fluoro-ll/8,l7a-dihydroxy-Z1-acetoxy=4-pregnene-3,ZO-dione in twelve mil liliters of chloroform and 0.1 milliliter of absolute alcohol was cooled to minus ten degrees centigrade in an icesalt bath. A stream of anhydrous hydrochloric acid was gently bubbled through the solution for 2.5 hours, during which period the temperature was maintained between minus five and minus fifteen degrees centigrade. The solution was then diluted with 25 milliliters of chloroform, washed with dilute aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure at sixty degrees centigrade. Crystallization of the residue from acetone-Skellysolve B hexanes gave 42 milligrams of the isomerized product, 6oz fluoro 115,17ot dihydroxy 21- acetoxy-4-pregnene-3,20-dione, which melted at 203 to 210 degrees centigrade.

PREPARATION 1 0 ot-fluoro-l 1d,] 70;,21-trihydr0xy-4-pregnene-3,20-dione (6 a-fluorohydrocortisone) A solution of 1.1 grams of 6a-flL1OI'O-1lfi,l7a-dl hydroxy-Z1-acetoxy-4-pregnene-3,ZO-dione, one gram of potassium bicarbonate, milliliters of methanol and fifteen milliliters of water were mixed together and purged with nitrogen to remove dissolved oxygen while stirring at 25 degrees centigrade for four hours. The solution was then neutralized by addition of acetic acid and distilled under vacuum to remove the methanol. The residue was extracted with 100 milliliters of methylene dichloride, and the extract was dried over sodium sulfate and passed through a column containing eighty grams of synthetic magnesium silicate. The fraction eluted with Skel'lysolve B hexanes plus twenty and thirty percent acetone weighed 770 milligrams, representing a yield of 77.5 percent. Recrystallization of a portion of this crude product from ethyl acetate-Skellysolve B hexanes gave crystals melting at 192 to 195 degrees centigrade.

Five 100-milliliter portions of a medium, in 250-milliliter Erlenmeyer flasks, containing one percent glucose, two percent corn .steep liquor (sixty percent solids) and tap water, were adjusted to a pH of 4.9. This medium was sterilized for 45 minutes at fifteen pounds per square inch pressure and inoculated with a one to two day growth of Septomyxa afiinis, A. T. C. C. 6737. The Erlenmeyer flask was shaken at room temperature (about 26 to 28 degrees Centigrade) for a period of three days. At the end of this period this 500-mi1liliter volume was used as an inoculum for ten liters of the same glucosecorn steep liquor medium which in addition contained ten milliliters of an antifoam compound (a mixture of lard oil and octadecanol). The fermenter was placed into the water-bath, adjusted to 28 degrees centigrade and the contents stirred (300 R. P. M.) and aerated (0.3 liter per minute of air to five liters of beer). After 24 hours of incubation, when a good growth had been developed, five grams of 6a-fiuoro-hydrocortisone acetate plus onehalf gram of 3-ketobisnor-4-cholen-22-a1, dissolved in 25 milliliters of dimethylformamide was added and the incubation carried out at the same temperature (28 degrees centigrade) and aeration for a period of 72 hours (final pH 8.3). The mycelium was filtered off and washed with water. The wash water was combined with the filtrate and the whole was extracted with three two-liter portions of a mixture of methylene chloride-ethyl acetate (3:1). Removal of the solvent by evaporation gave 5.25 grams of crude solid which was triturated twice with four milliliters of methylene chloride to give 24 grams of 1- dehydro-6a-fluorohydrocortisone of melting point 198 to 203 degrees centigrade. The analytical sample, recrystallized from acetone, melted at 202 to 204 degrees centigrade. Analysis gave [@1 plus 73 degrees (dioxane) and the following:

Analysis.Calcd. for C i-1 0 1 C, 66.65; H, 7.10; F, 5.02. Found: C, 66.68; H, 7.19; F, 5.49.

Substitution of the 6fl-epimer for the starting material above is productive of 1-dehydro-Gfi-fiuorohydrocortisone. The 6,8-epimer can be converted to the 6a-epimer following the procedure of Preparation 9.

asserts 9 PREPARATION 12 61ruoro-l 16,17or-dihydrx3 -21 -acet0xy-1 ,4-pregnadierre- 3,20-dione (1 -dehydr0-6a-fls arohydrocortisone acetate) A solution of two grams of 1-dehydro-6muorohydrocortisone in ten milliliters of pyridine and ten milliliters of acetic ian'hydride was allowed to stand at room temperature for seventeen hours, and was then poured into a mixture of ice and water.

degrees (acetone) and the following:

Analysis.Calcu1ated for C H O F: C, 65.70; H, 6.95; F, 4.52. Found: C, 65.58; H, 7.16; F, 4.39.

PREPARATION 13 dau oro-l 7u-hydroxy-2l .-aceto;cy-1 ,4,9(] 1 )-pregnatriene- 3,20-di0ne To a solution of 1.05 grams of l-dehydro-6a-fluorohydrocortisone acetate in ten milliliters of pyridine was added 0.5 17 gram of N-bromoacetamide. The mixture was allowed to stand under nitrogen for fifteen minutes, at which time it was cooled to five degrees centigrade. While stirring, sulfur dioxide was passed over the surface until the solution gave no color change with acidified starch-iodide paper. The temperature of the reaction mixture was not allowed to go above twenty degrees centigrade during the sulfur dioxide addition. The mixture was then poured into 100 milliliters of ice-water, resulting in precipitation of 977 milligrams of Got-fluoro- 17a hydroxy 21 acetoxy-1,4,9(1l)-pregnatrierre-3,20- dione, melting point 186 to 196 degrees centigrade (with decomposition). The analytical'sample melted at 213 to 216 degrees centigrade (with decomposition). Analysis 'gave fal 'plus 34' degrees (acetone) and the following:

Analysis.--Calcd. for C I-1 0 1 C, 68.64; H, 6.76; F, 4.72. Found: C, 68.85; H, 6.86; F, 4.72.

PREPARATION 14 To a solution of 1.27 grams of 6u-fiu0I0-17ac-hYdf0XY- 21-acetoxy-1,4,9(11)-pregnatriene 3,20 dione in I 19.5 milliliters of methylene chloride was added 38 milliliters of tertiary butyl alcohol, a solution of three milliliters of 72 percent perchloric acid in 22.5 milliliters of water, and a solution of 0.55 gram of N-bromoacetamide in 9.6 milliliters of tertiary butyl alcohol. After stirring for fifteen minutes, a solution of 0.55 gram of sodium sulfite in thirty milliliters of water was added and the mixture concentrated under reduced pressure at sixty degrees centigrade until crystallization occurred. After cooling in an ice bath, 100 milliliters of water was added with stirring. On filtering the crystalline product, followed by washing with water and drying, a yield of 1.59 grams of essentially pure 6u-fluoro-9a-bromod113,17- dihydroxy-Zl-acetoxy-l,4-pregnadiene-3,20-dione, melting point 188 to 191 degrees centigrade (with decomposi- "tion) was obtained. The product was used in the succeeding example without further purification.

Substitution of N-iodosu-ccinimide for the N-bromoaeetamide in the foregoing reaction is productive of the corresponding 9a-i0d0 product.

PREPARATION 15 6 atiara-9B,] I fi-oxido-I 7a-hya'roxy-21 -acetoxy-1,4-pregnadiene-3,20-di0ne A mixture of 1.749 grams of '60t-fll10I'O-90t-b1'OII1Q- 1 15,17a-dihydroxy-2l-acetoxy-1,4-pregnadiene-3,20-dione (1 dehydro-6a-fluoro-9u-bromohydrocortisone acetate),

' eighteen hours.

10 1.749 grams of potassium acetate, and fifty milliliters of acetone was stirred and heated at reflux temperature for The reaction mixture was then concentrated to about one-half the original volume, cooled and poured into 300 milliliters of water to give 1.303 grams of 6or-iluoro 96,116 oxido-17a-hydroxy-21-acetoxy-1,4- pregnadiene-3,20-dione, melting point 234 to 238 degrees centigrade (with decomposition). The analytical sample, recrystallized from acetone, melted at 257 to 260 degrees centigrade. Analysis gave [uJ plus '70 degrees (acetone) and the following:

Analysis-Calcd. for C H O F: C, 66.01; H, 6.50; F, 4.54. Found: C, 65.73; H, 6.58; F, 3.87.

PREPARATION l6 6a,9o:. a'z'fluoro 116,170; dihydroxy 21 acetoxy- 1,4-pregnadiene-3,ZO-dione (1-dehydr0 6ct,9a-diflu0r0- hydrocortisone acelate) To 5.2 grams of liquid hydrogen fluoride cooled in Dry-Ice bath, was added, portion-wise, a slurry of 2.276 grams of 6a-fluoro-9BJlfl-oxidd17a-hydroxy-21acetoxy- 1,4-pregnadiene-3,20-dione in nine grame of tetrahydrofuran (distilled over NaOH) and 28 milliliters of methylene chloride which had similarly been cooled in a Dry- Ice bath. The steroid dissolved completely. After standing at zero to five degrees centigrade for seventeen hours, the reaction mixture was poured slowly into a stirred mixture of 500 milliliters of water and 25 grams of sodium bicarbonate. The mixture was stirred for a few minutes, and the product was extracted with three IOU-milliliter portions of methylene chloride. The methylene chloride solution was washed with water, dried, and chromatographed over synthetic magnesium silicate. The fraction eluted from the column with fifteen and twenty percent acetone in Skellysolve B hexanes was recrystallized from ethyl acetate-Skellysolve B hexanes to give 1.342 grams of product, melting point 238 to 242 degrees centigrade. The analytical sample melted at 239 to 242 degrees centigrade. Analysis gave [al plus 91 degrees (acetone) and the following:

Analysis.Calcd. for C H O F C, 63.00; H, 6.44; F, 8.67. Found: C, 63.23; H, 6.82; F, 8.14.

Substitution of aqueous hydrogen chloride for the hydrogen fluoride above is productive of the corresponding 9a-cl1loro product.

PREPARATION 17 60:,904 difluoro ]1[5,]7u,2] trihydroxy 1,4 pre nadiene-3,20-dione (1-ziehydro-6a,9ot-difluorohydrocortisone) Nitrogen was bubbled through a solution of 1.4 grams of 6a,9a-difluoro-1 l t3,17u-dihydroXy-2l-acetoxy-l,4-pregnadiene 3,20 dione (l dehydro 60,9u difluorohydrocortisone acetate) in 140 milliliters of methanol for fifteen minutes. To this was added a solution of 1.4 grams of potassium bicarbonate in 17.5 milliliters of water likewise treated with nitrogen. After stirring under nitrogen for five hours, the base was neutralized by the addition of 1.5 milliliters of acetic acid in forty milliliters of water. The mixture was then concentrated under reduced pressure at 55 degrees centigrade until crystallization started. The slurry was then cooled in an ice bath, diluted with milliliters 'of water, and filtered to give 0.892. gram of 6a,9a-difluoro-11;3, 17a,21-trihydroxy-1,4- pregnadiene-3,20-dione (1-dehydro-6u,9a-difluorohydrocortisone), melting point 232 to 242 degrees centigrade (with decomposition). The analytical sample melted at 250 to 257 degrees centigrade (with decomposition). Analysis gave [otl plus 84 degrees (acetone) and the following:

Analysis.--Calcd. for C H O F C, 63.62; H, 6.61; F, 9.59. Found: C, 62.76; H, 7.10; F, 9.41.

In the same manner, hydrolysis of 6(X-fil10l'0-90L-Ch101'0- .1113, 1700 dihydroxy 21 acetoxy 1,4 pregnadiene- 3,20-dione with potassium bicarbonate in aqueous methanol under nitrogen'yields 60-fillOIO-9OL-Chl01O-11fi,170t, 21-trihydroxy-1,4-pregnadiene-3,20-di0ne and 60t-fluoro- 90 bromo 1113,1700 dihydroxy 21 acetoxy 4 pregnene 3,20 dione yields 60 fluoro 90 bromo- 1 118,17a,21-trihydroxy-1,4-pregnadiene-3 ,20-dione.

PREPARATION 18 6a,9a difiuoro 17oz hydroxy 21 acetoxy 1,4- pregnadiene-3,l1,20-trine (1-dehydro-6a,9a-difizzorocortisone acetate) A solution was prepared containing 0.5 gram of 601,900- difluoro 11,8, 17a dihydroxy 21 acetoxy 1,4 pregnadiene 3,20 dione (1 dehydro 60,9l! difiuorohydrocortisone acetate), 0.15 gram of chromium trioxide, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture was stirred and maintained at room temperature for eight hours. Thereafter, the excess oxidant was destroyed by addition'of methanol and the mixture was poured into fifty milliliters of ice water. The resulting precipitate was collected on a filter and recrystallized from ethyl acetate-Skellysolve B hexanes to give 6a,90t-difluoro-170t-hydroxy-21-acetoxy-1,4- pregnadiene-3,1 1,20-trione.

In the same manner 60L-flllOIO-90t-Chi0I'O-1113,170t-dlhydroxy-21-acetoxy-1,4-pregnadiene-3,20-dione oxidized with chromium trioxide in acetic acid yielded 60t-fluoro- 90: chloro 17oz hydroxy 21 acetoxy 1,4 pregnadiene-3,11,20-trione and 6a-fiuoro-9a-bromo-l15,171 dihydroxy-Zl-acetoxy-l,4-pregnadiene-3,20-dione yielded 60: fluoro 9a bromo 170: hydroxy 21 acetoxy- 1,4-pregnadiene-3,1 1,20-trione.

PREPARATION 19 60:,90: difiuoro 170:,2] dilzydroicy 1,4 pregnadiene- 3,11 ,ZO-trione (I dehydro-6a,9a-diflu0r0cortis0ne) Following the procedure of Preparation 17 but substituting 1-dehydro-6a,90t-ditluorocortisone acetate as the starting material therein is productive of 1-dehydro-60c, 9a-difluorocortisone. Similarly, substituting 60L-fluOI'O-90tchloro 170: hydroxy 21 acetoxy 1,4 pregnadiene- 3,11,20-trio-ne is productive of 60c-fiuoro-9a-chloro- 17u,21-dihydroxy-1,4-pregnadiene-3,11,20-trione and 60:- fluoro 90c bromo 17:0 hydroxy 21 acetoxy 1,4- pregnadiene-3,l1,20-trione is productive of 6tr-fluoro-90tbromo-17mll-dihydroxy-l,4-pregnadiene-3 ,11,20-trione.

PREPARATION 20 60c fluoro 9a bromo 1.1fl,17oc,21 trihydroxy 1,4- pregnadiene-3,20-dione I -dehydr0-6a-flu0r0-90-br0- .mohydrocortisone) Following the procedure of Preparation 17, substitution of 1*iehydro-600-fiuoro-9tx-bromohydrocortisone acetate from Preparation 14 for l-dehydro-60,9a-difiuorohydrocortisone acetate is productive of 1-dehydro-6a-fiuoro 9a-bromohydrocortisone. Alternatively, the removal of the acetate from 60t-fluoro-9u-bromohydrocortisone acetate to produce 60t-fiuoro-9a-bromohydrocortisone is accomplished under acid conditions, such as, for example, methanolic hydrochloric acid.

PREPARATION 21 6fi-epimers Substituting 6,8-fluorohydrocortisone acetate for the starting material in Preparation 11 and retaining the 618 configuration in subsequent steps by careful maintenance of near neutral reaction conditions, 6,8-epimers, such as 1 dehydro 65,90: difluorohydrocortisone, l dehydro 6 3 fluoro 9a chlorohydrocortisone, 1 dehydro 6t? fluoro 9a bromohydrocortisone, 1 dehydro 6 8 90 difiuorocortisone, 1 dehyro 6,8 fluoro- 9C6 chlorocortisone and 1 dehydro 6,3 fluoro 90c- 12 bromocortisone, are produced. The thus obtained 613- epimers yield the 60t-epimers by treatment with acid according to the procedure of Preparation 9.

EXAMPLE 1 6a,90z-difluor0-I 15,] 701,21 -trihydroxy-1 ,4-pregnadiene- 3,20-dione 21 -methanesulfonate degrees centigrade for seventeen hours, and was then poured into milliliters of cold five percent hydrochloric acid to precipitate the solid mesylate. The product, after filtration, weighed 0.832 gram and had a melting point of 157 degrees centigrade (with decomposition).

EXAMPLE 2 60,9oc difiuoro 11,13,170: dihydroxy-Z1-i0d0-L4-pregnadz'ene-3,20-di0ne (III) and 6 a,90z-diflu0r0-1 1 5,1 7u-dihydroxy-I,4-pregnadierte-3,20-di0ne (IV) To a solution of 332 milligrams of 606,9(X-dlfill01'0- 1l/3,l7oz,21 trihydroxy 1,4-pregnadiene 3,20-dione 21- methane sulfonate (II) in eightmilliliters of acetone was added a solution of 332 milligrams of sodium iodide in eight milliliters of acetone. The mixture was stirred at reflux for fifteen minutes and was then evaporated to dryness with a stream of nitrogen. The residue containing 60t,9OL difiuoro-11,8,17a-dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione (III) was dissolved in eight milliliters of acetic acid and stirred for 45 minutes. A solution of 400 milligrams of sodium thiosulfate in eight milliliters of Water was added to the acetic acid solution, then 100 milliliters of ice and water was added. The resulting solid, isolated by filtration, weighed 272 milligrams, and was chromatographed over synthetic magnesium silicate, then crystallized from acetone to give 127 milligrams of 60t,90:-difluoro-11p,170-dihydroxy-1,4- pregnadiene-3,20-dione (IV), melting at 288 to 295 degrees centigrade. The analytical sample melted at 296 to 300 degrees centigrade. Analysis gave [a1 plus 58 degrees (pyridine) and the following:

Analysis.-Calcd. for C H O F C, 66.30; H, 6.89; F, 9.99. Found: C, 65.88; H, 6.76; F, 9.39.

The 606,904 difiuoro 1113,1700 dihydroxy-21-iodo-l,4- pregnadiene-3,20-dione (III) can be recovered in purified form by recrystallization from methylene chloride.

EXAMPLE 3 6 0t,90t-diflu0r0-1 70t-hydr0xy-1,4-pregnadiene-3,11 ,20- trione (V) A solution is prepared containing 0.5 gram of 60:,941- difiuoro 1113,17a dihydroxy,1,4-pregnadiene-3,20-dione (IV), 0.15 gram of chromium trioxide, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture is stirred and maintained at room temperature for eight hours. Thereafter excess oxidant is destroyed by the addition of methanol and the mixture is poured into fifty milliliters of ice water. The thus precipitated 60,90 difiuoro 17a hydroxy 1,4-pregnadiene-3,11,20- trione (V) is collected on a filter, washed with water, and dried.

Alternatively, starting with 6a,90-difluoro-17a,21-dihydroxy-l,4-pregnacliene-3-11,20-trione from Preparation 17 and reacting this with methanesulfonyl chloride to produce the ZI-mcthanesulfonate, then treating the 21- methanesulfonate with sodium iodide in acetone to produce the 21-iodide, and treating the 21-iodide with sodium thiosulfate, as shown in Examples 1 and 2, is productive of 60,90t difiuoro hydroxy-1,4-pregnadiene-3,11,20-trione (V). I

Inthe same manner given in Examples 1 and 2, reacting in pyridine solution 6oL-fll1O1'O-9oc-Cl1l0r0-1113,17oz,2ltn'hydroxy-1,4-pregnadiene-3,20-dione, from Preparation 15, with methanesulfonyl chloride, reacting the thus produced 21-methanesulfonate with sodium iodide in acetone to produce the 21-iodide, and reducing the 21-iodide with aqueous sodium thiosulfate is productive of 6u-fiu01Q-9achloro 11B,17a dihydroxy 1,4-pregnadiene-3,20-dione. Similarly, starting with 6uc-fi110IO-9a-b1Om0-11l3,17ot,21- trihydroxy-1,4-pregnadiene-3,20-dione is productive of 6oz fluoro-9a-bromo-1 1,8,17u-dihydroxy-1,4-pregnadiene- 3,20-dione.

EXAMPLE 5 6o: 7 fluoro 9a-chl0r0-17a-hydr0xy-1,4-pregnadiene-3,11,

20 trione and 6a fluoro 9a-br0mo-17a-hydr0xy-L4- pregnadiene-3J1,20-tri0ne In the same manner given in Example 3, reacting 6a fluoro-9a-chloro-11B,-17a-dihydroxy-1,4-pregnadiene- 3,20-dione with chromium trioxide in acetic acid and water is productive of 6a-fluoro-9a-chloro-17a-hydroxyl,4-pregnadiene-3,l1,20-trione. Similarly starting with 60: fluoro-9a-bromo-l1,8,17oa-dihydroxy-1,4-ptegnadiene 3,20-dione is productive of 6u-fiuoro-9ot-bromo-l7ot-hydroxy-1,4-pregnadiene-3,11,20-trione. Alternatively, starting with 6ot-fluoro-9a-chloro-l7u,2l-dihydroxy-l,4-pregnadiene-3,11,20-trione from Preparation 16 and reacting this with methanesulfonyl chloride to produce the 21- methanesulfonate, then treating the 21-methanesulfonate with sodium iodide in acetone to produce the 2l-iodide, and treating the 21-iodide with sodium thiosulfate as shown in Examples 1 and 2, is productive of 60t-flll0l'Q-90tv 'chloro-17ot-hydroxy-1,4-pregnadienc-3,l1,20-trione. Similarly starting with 6a-fluoro-9a-bromo-l7a,21-dihydroxy- 1,4-pregnadiene-3,11,20-trione is productive of 6oc-fl1101'0 9a-bromo-17ot-hydroxy-1,4-pregnadiene-3,1 1,20-trione.

EXAMPLE 6 6fl-epimers Substituting 6fl,9u-difluoro-l 1fi,17u,21-trihydroXy-1,4- pregnadiene 1 3,20-dione (1dehydro-6B,9ot-difluorohydrocortisone) for the starting material in Example 1 and retaining the 6,8 configuration in subsequent steps by careful maintenance of near neutral reaction conditions, 65- epimers such as 6,8,9a-difluoro-11,B,l7ot-dihydroxy1,4- pregnadiene-3,20-dione, 6fl-fluOrO-9oc-chl0r0-l16,17a-dihydroxy-1,4-pregnadiene-3,20-dione, 6B-fiuoro-9ot-bromo- 115,170 dihydroxy 1,4-pregnadiene-3,ZO-dione, 65,90:- difluoro-17 a-hydroxy-1,4-pregnadiene6,1 1,20-trione, 6 8- fluoro 90c chloro-17a-hydroxy-1,4-pregnadiene-3,11,20- trione and 6B-fluo1'o-9ot-bromo-17a-hydroxy-1,4-pregnadiene-3,l1,20-trione are produced, which can be isolated from the reaction mixture. The thus obtained 6/3 epimers yield the 6ot-epimers by treatment with an acid or base in an organic solvent.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art. The invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of 1 dehydro 6 fluoro 90c halo-2l-desoxyhydrocortisome and l dehydro 6 fluoro 90c halo 2l-desoxycortisone wherein the 9a-ha1ogen atom is of atomic weight between seventeen and eighty, inclusive.

2. A compound selected from the group consisting of 1 dehydro 60 fluoro 90c halo-2l-desoxyhydrocortisone and l dehydro 60c fluoro 90c halo-21-desoXy- 14 cortisone wherein the 9a-halogen atom is of atomic weight between seventeen and eighty, inclusive.

3. 1 dehydro 6a fluoro c halo 21 desoxyhydrocortisone wherein the 9a-halogen is of atomic weight between seventeen and eighty, inclusive.

4. 1 dehydro 6a,9a difluoro 21 desoxyhydrocortisone.

5. l dehydro 6a fluoro 9a chloro 21 desoxyhydrocortisone.

6. 1 dehydro 6a fluoro 9a bromo 21 desoxyhydrocortisone.

7. l dehydro 6oz fluoro 9a halo 21 desoxycortisone wherein the halogen is of atomic weight between seventeen and eighty, inclusive.

8. 1. dehydro 6:1,9a difluoro 21 desoxycortisone.

9. 1 dehydro 6a fluoro 9oz chloro 21 desoxycortisone.

10. 1 dehydro 6a fluoro 9a brorno 21-desoxycortisone.

11. A compound of the formula RI CH3 wherein R is a hydrocarbon radical containing from one to ten carbon atoms, inclusive, and R is selected from the group consisting of hydroxy and keto, and X is halogen of atomic weight between seventeen and eighty, inclusive.

l2. 60:,9oc difluoro 1lfi,17a,21-trihydroxy-l,4-preg nadiene-3,20-dione ZI-methanesulfonate.

13. A compound of the formula (llHzoH C=O l----0H R CH3 wherein R is a member selected from the group consisting of hydroXy and keto and X is halogen of atomic weight between seventeen and eighty, inclusive, with an organic sulfonyl halide to produce the corresponding 21- organic acid sulfonate, reacting the said 2l-organic acid sulfonate with an iodinating agent to produce the correspondingZl-iodo compound, and reacting the said 21- iodo compound with a reducing agent to produce the corresponding 2l-desoxy compound.

16. A process for the production of l-dehydro-G-fluoro- 9a-halo-2l-desoxyhydrocortisone which comprises: treat- 9OC-ha10-21- desoxydrocortisone.

17. A process for the production of l-dehydro-6ufluoro-9a-halo 21 desoxyhydrocortisone, wherein the halogen is of atomic weight seventeen to eighty, inclusive, which comprises: treating 1 dehydro 60c fiuoro 9ahalohydrocortisone with methane sulfonyl chloride to produce the Zl-methanesulfonate, reacting the said 21-methanesulfonate with sodium iodide to produce l-dehydro- 6a fiuoro 90c halo 21 iodo 21 desoxyhydrocortisone, and reacting the said 21-iodo compound with an alkali metal thiosulfate to produce l-dehydro-6a-fluoro- 9a-halo-2l-desoxyhydrocortisone.

18. A process for the production of 1-di3hydIO-6C5,9adifluoro-2l-desoxyhydrocortisone which comprises: treating 1-dehydro-6a,9u-difiuorohydrocortisone with methanesulfonyl chloride to produce the 21-methanesulfonate, treating the said 21--methanesulfonate with sodium iodide to give 1-dehydro-6a,9zx-difluoro-21 iodo 21 desoxyhydrocortisone, and reacting the said 1-dehydro-21-iodo compound with an alkali metal thiosulfate to produce 1-dehydro-6a,9u-difiuoro-2l-desoxyhydrocortisone.

19. A process for the production of l-dehydro-6-fluoro- 9a-halo-2l-desoxycortisone wherein the halogen is of atomic weight seventeen to eighty, inclusive, which comprises: treating 1-dehydro-6-fiuoro-9ot-halohydrocortisone with an organic sulfonyl halide to produce the corresponding 21-organic acid sulfonate, reacting the said 21-0rganic acid sulfonate with an iodinating agent to produce 1-dehydro-6-fluoro-9u-halo-21-iodo-21-desoxyhydrocortisone, reacting the said 21-iodo compound with a reducing agent to produce 1-dehydro-6-fluoro-9a-halo- 21-desoxyhydrocortisone, and reacting the said l-dehydro-6-fluoro-9ot-halo-2l-desoxyhydrocortisone with an oxidizing agent to produce l-dehydro-6-fiuoro-9a-halo- 21-desoxycortisone.

20. A process for the production of 1-dehydro-6afluoro-9a-halo-2l-desoxycortisone,' wherein the halogen is of atomic weight seventeen to eighty, inclusive, which comprises: treating l-dehydro-6zx-fluoro-9a-halo-2l-desoxyhydrocortisone' with methanesulfonyl chloride to produce the ZI-methanesulfonate, reacting the said 21- methanesulfonate with sodium iodide to produce l-dehydro 6oz fluoro 90c halo 21 iodo 21 desoxyhydrocortisone, reacting the said 21-iodo compound with an alkali metal thiosulfate to produce 1-dehydro-6ocflu0ro-9a -halo-2l-desoxyhydrocortisone, and reacting the said 1-dehydro-6a-fiuoro-9u-halo-2l-desoxyhydrocortisone with chromium trioxide to produce 1-dehydro-6a-flu0ro- 9u-halo-2l-desoxycortisone.

21. A process for the production of l-dehydro-6a,9adifluoro-2l-desoxyhydrocortisone which comprise: treating 1-dehydro-6a,9ot-difluorohydrocortisone with methanesulfonyl chloride to produce the ZI-methanesulfonate, reacting the said 21-methanesulfonate with'sodium iodide to produce 1-dehydro-6vt,9a-difiuoro-2l-iodo-21-desoxyhydrocortisone, reacting the said 1-dChydIO-606,90t-difiuoro-Z1-iodo-2l-desoxyhydrocortisone with an alkali metal thiosulfate to produce 1-dehydro-6a,9u-difluoro- 2l-desoxyhydrocortisone and reacting the said l-dehydro- 6a,9a-difluoro-2l-desoxyhydrocortisone with chromium trioxide to produce 1-dehydro-6a,9a-difluoro-2l-desoxycortisone.

22. A process for the production of 1-dehydro-6- fluoro-9a-halohydrocortisone ZI-organic acid sulfonate which comprises: treating 1-dehydro-6-fiuoro-9a-halohydrocortisone with an organic sulfonyl halide.

23. A process for the production of 1-dehydro-6-fluoro- 9a-halo-21-iodo-2l-desoxyhydrocortisone which comprises: treating l-dehydro-6-fluoro-9a-halohydrocortisone 21-organic acid sulfonate with an iodinating agent.

24. A process for the production of 1-dehydro-6-fluoro- 9a-halo-2l-desoxyhydrocortisone which comprises: treating 1-dehydro-6-fluoro-9a-halo-2l-iodo-Zl-desoxyhydrocortisone with a reducing agent.

25. A process for the production of l-dehydro-6a,9adifluoro-2l-desoxyhydrocortisone which comprises; treating 1-dehydro-6u,9a-difiuoro-21-iodo-21-desoxyhydrocortisone with an alkali metal thiosulfate.

26. A process for the production of l -dehydro-6-fluoro- 9a-halo-21-desoxycortisone which comprises: treating 1-dehydro-6-fluoro-9a-halo-2l-desoxyhydrocortisone with an oxidizing agent.

27. A process for the production of l-dehydro-6a,9a-difiuoro-Zl-desoxycortisone which comprises: treating 1- dehydro 60:,9a difluoro 21-desoxyhydrocortisone with chromium trioxide.

References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1 - DEHYDRO - 6 - FLUORO - 9A - HALO-21-DESOXYHYDROCORTISONE AND 1 - DEHYDRO - 6 - FLUORO - 9A - HALO - 21-DESOXYCORTISONE WHEREIN THE 9A-HALOGEN ATOM IS OF ATOMIC WEIGHT BETWEEN SEVENTEEN AND EIGHTY, INCLUSIVE. 